The largest risk factor for developing cancer is age. Age also poses the largest risk for developing many of the degenerative pathologies of aging. This exploratory application will test the idea that cellular senescence - a tumor suppressive response - is a basic aging process that links the development of cancer with the development of age-related degenerative disease. We propose to critically test the idea that senescent cells are important determinants of cancer risk and contribute to the age-dependent rise in cancer incidence. We will use two newly developed mouse models to: 1) induce senescence in a tissue-specific and temporally-controlled manner, and 2) eliminate senescent cells at will. We will use these models in conjunction with a well-described two-stage skin carcinogenesis protocol that will allow us to distinguish the effects of senescent cells on cancer initiation from effects on cancer promotion. We will also determine the extent to which senescent cells mediate the effects of natural aging on cancer development. The results will pave the way to applying the principles we uncover in skin carcinogenesis to a wide variety of other cancers. They will also provide a strong rationale for developing novel preventive or interventional strategies aimed at eliminating senescent cells, or selectively ameliorating their deleterious effects, from tissues that are at risk for developing malignancies. PUBLIC HEALTH RELEVANCE: Age is the largest single risk factor for developing cancer, but the reasons for the steep rise in cancer with age are incompletely understood. We will use two novel mouse models to critically test the idea that senescent cells, which accumulate with age as a consequence of oncogenic stress, are crucial determinants of the development of cancer in older organisms. Our proposed studies will provide crucial insights into the link between cancer and aging, and identify novel strategies for cancer prevention and interventions.